Ayşegül Yildiz

The International Society for Bipolar Disorders (ISBD) Task Force Report on Antidepressant Use in Bipolar Disorders

OBJECTIVE The risk-benefit profile of antidepressant medications in bipolar disorder is controversial. When conclusive evidence is lacking, expert consensus can guide treatment decisions. The International Society for Bipolar Disorders (ISBD) convened a task force to seek consensus recommendations on the use of antidepressants in bipolar disorders. METHOD An expert task force iteratively developed consensus through serial consensus-based revisions using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new or reworded items and items that needed to be rerated. This process resulted in the final ISBD Task Force clinical recommendations on antidepressant use in bipolar disorder. RESULTS There is striking incongruity between the wide use of and the weak evidence base for the efficacy and safety of antidepressant drugs in bipolar disorder. Few well-designed, long-term trials of prophylactic benefits have been conducted, and there is insufficient evidence for treatment benefits with antidepressants combined with mood stabilizers. A major concern is the risk for mood switch to hypomania, mania, and mixed states. Integrating the evidence and the experience of the task force members, a consensus was reached on 12 statements on the use of antidepressants in bipolar disorder. CONCLUSIONS Because of limited data, the task force could not make broad statements endorsing antidepressant use but acknowledged that individual bipolar patients may benefit from antidepressants. Regarding safety, serotonin reuptake inhibitors and bupropion may have lower rates of manic switch than tricyclic and tetracyclic antidepressants and norepinephrine-serotonin reuptake inhibitors. The frequency and severity of antidepressant-associated mood elevations appear to be greater in bipolar I than bipolar II disorder. Hence, in bipolar I patients antidepressants should be prescribed only as an adjunct to mood-stabilizing medications.

Efficacy of Antimanic Treatments: Meta-analysis of Randomized, Controlled Trials

We conducted meta-analyses of findings from randomized, placebo-controlled, short-term trials for acute mania in manic or mixed states of DSM (III–IV) bipolar I disorder in 56 drug–placebo comparisons of 17 agents from 38 studies involving 10 800 patients. Of drugs tested, 13 (76%) were more effective than placebo: aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, lithium, olanzapine, paliperdone, quetiapine, risperidone, tamoxifen, valproate, and ziprasidone. Their pooled effect size for mania improvement (Hedges’ g in 48 trials) was 0.42 (confidence interval (CI): 0.36–0.48); pooled responder risk ratio (46 trials) was 1.52 (CI: 1.42–1.62); responder rate difference (RD) was 17% (drug: 48%, placebo: 31%), yielding an estimated number-needed-to-treat of 6 (all p<0.0001). In several direct comparisons, responses to various antipsychotics were somewhat greater or more rapid than lithium, valproate, or carbamazepine; lithium did not differ from valproate, nor did second generation antipsychotics differ from haloperidol. Meta-regression associated higher study site counts, as well as subject number with greater placebo (not drug) response; and higher baseline mania score with greater drug (not placebo) response. Most effective agents had moderate effect-sizes (Hedges’ g=0.26–0.46); limited data indicated large effect sizes (Hedges’ g=0.51–2.32) for: carbamazepine, cariprazine, haloperidol, risperidone, and tamoxifen. The findings support the efficacy of most clinically used antimanic treatments, but encourage more head-to-head studies and development of agents with even greater efficacy.

Protein Kinase C Inhibition in the Treatment of Mania: A Double-blind, Placebo-Controlled Trial of Tamoxifen

CONTEXT Findings that protein kinase C (PKC) activity may be altered in mania, and that both lithium carbonate and valproate sodium inhibit PKC-associated signaling in brain tissue, encourage development of PKC inhibitors as candidate antimanic agents. OBJECTIVE To perform a controlled test of antimanic efficacy of the centrally active PKC inhibitor tamoxifen citrate. DESIGN Three-week, randomized, double-blind, placebo-controlled, parallel-arms trial. SETTING A university medical center inpatient psychiatric unit in Izmir, Turkey. PATIENTS Sixty-six patients aged 18 to 60 years, diagnosed as having DSM-IV bipolar I disorder on the basis of the Structured Clinical Interview for DSM-IV, currently in a manic or mixed state, with or without psychotic features, with initial scores on the Young Mania Rating Scale (YMRS) greater than 20. INTERVENTION Treatment with tamoxifen or identical placebo tablets for up to 3 weeks. Adjunctive lorazepam was allowed up to 5 mg/d. MAIN OUTCOME MEASURES Primary: change in YMRS scores; secondary: change in Clinical Global Impressions-Mania scores, weekly ratings of depression and psychosis, and adjunctive use of lorazepam. RESULTS The 21-day trial was completed by 29 of 35 subjects randomized to receive tamoxifen (83%) and 21 of 31 given placebo (68%) (P = .25). Intent-to-treat analysis of available measures on all 66 subjects indicated that tamoxifen treatment yielded mean decreases in scores on the YMRS and Clinical Global Impressions-Mania of 5.84 and 0.73 point per week, respectively, compared with mean increases of 1.50 and 0.10 point per week, respectively, with placebo; both drug-placebo contrasts differed significantly (P < .001). CONCLUSIONS Tamoxifen demonstrated antimanic properties and was remarkably well tolerated. The findings encourage further clarification of the role of PKC in the pathophysiologic mechanism of bipolar I disorder and development of novel anti-PKC agents as potential antimanic or mood-stabilizing agents. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00411203 and isrctn.org Identifier: ISRCTN97160532.

Pharmacological management of agitation in emergency settings.

Objective: To review, firstly, published studies comparing classic antipsychotics, benzodiazepines, and/or combination of both; and secondly, available data on the use of atypical antipsychotic medications in controlling agitation and aggressive behaviour seen in psychiatric patients in emergency. Method: In the first review, studies comparing antipsychotics, benzodiazepines, and combination of both; and in the second review, efficacy trials of atypical antipsychotics that include an active and/or inactive comparator for the treatment of acute agitation were identified and reviewed. Data from clinical trials meeting the inclusion criteria were summarised by recording improvement rates, definition of improvement, and timing of defined improvement for individual studies. Results: In the first review, 11 trials were identified meeting the inclusion criteria, eight with a blind design. The total number of subjects was 701. These studies taken together suggest that combination treatment may be superior to the either agent alone with higher improvement rates and lower incidence of extrapyramidal side effects. In the review of atypical antipsychotic agents as acute antiagitation compounds, five studies were identified, three with a blind design. The total number of subjects was 711, of which 15% (104) was assigned to the placebo arm. This review found atypical antipsychotics to be as effective as the classic ones and more advantageous in many aspects. Conclusion: Atypical antipsychotics such as risperidone, ziprasidone, and olanzapine with or without benzodiazepines should be considered first in the treatment of acute agitation. If these agents are not available the combination of a classic antipsychotic and a benzodiazepine would be a reasonable alternative. An oral treatment should always be offered first for building up an alliance with the patient and suggesting an internal rather than external locus of control.

31P Nuclear magnetic resonance spectroscopy findings in bipolar illness: a meta-analysis.

Published literature comparing 31P MR brain spectra of bipolar patients to healthy controls was evaluated, focusing on phosphomonoester (PME)/phosphodiester (PDE) resonance areas because these metabolites are related to membrane phospholipids and membrane defects in bipolar disorder have been suggested. Studies comparing PME and/or PDE values of bipolar subjects to values observed in healthy controls were reviewed. Data from the studies meeting our inclusion criteria (8 reports involving 139 bipolar and 189 comparison subjects) were grouped according to the mood state of the subjects. Meta-analyses of data were performed to compare PME and PDE levels of euthymic bipolar patients to healthy controls, as well as comparing PME levels during euthymia in bipolar subjects to values observed during manic and depressed states. The PME values of euthymic bipolar patients were found to be significantly lower than PME values of healthy controls. Depressed bipolar patients had significantly higher PME values in comparison to euthymic bipolar patients. No significant difference could be detected between the PDE values of bipolars and controls. This meta-analysis found support for trait- and possibly state-dependent abnormalities of membrane phospholipid metabolism, which may reflect a dysregulation in brain-signal transduction systems of relevance in bipolar illness.

Age at onset versus family history and clinical outcomes in 1,665 international bipolar-I disorder patients

Early onset in bipolar disorder (BPD) has been associated with greater familial risk and unfavorable clinical outcomes. We pooled data from seven international centers to analyze the relationships of family history and symptomatic as well as functional measures of adult morbidity to onset age, or onset in childhood (age <12), adolescence (12-18), or adulthood (19-55 years). In 1,665 adult, DSM-IV BPD-I patients, onset was 5% in childhood, 28% in adolescence, and 53% at peak ages 15-25. Adolescent and adult onset did not differ by symptomatic morbidity (episodes/year, percentage of months ill, co-morbidity, hospitalization, suicide attempts) or family history. Indications of favorable adult functional outcomes (employment, living independently, marriage and children, and a composite measure including education) ranked, by onset: adult > adolescent > child. Onset in childhood versus adolescence had more episodes/year and more psychiatric co-morbidity. Family history was most prevalent with childhood onset, similar over onset ages 12-40 years, and fell sharply thereafter. Multivariate modeling sustained the impression that family history and poor functional, but not symptomatic, outcomes were associated with younger, especially childhood onset. Early onset was more related to poor functional outcomes than greater symptomatic morbidity, with least favorable outcomes and greater family history with childhood onset.

Age onset of psychotic versus non-psychotic bipolar illness in men and in women

OBJECTIVE To investigate the relationship between psychotic symptoms and age at onset of bipolar illness. METHOD The charts of bipolar patients treated at the Massachusetts General Hospital Bipolar Clinic were reviewed for age of first affective episode, demographics and history of psychotic symptoms. RESULTS Data was obtained for 328 bipolar patients (56.7% females) of whom 42% had psychotic symptoms sometime through the course of their illness. Overall, there was no significant difference in age of onset between the psychotic and non-psychotic groups. Additional analysis carried out separately by gender found significant difference for males but not for females. Age at onset for psychotic males was significantly lower than non-psychotic males. Psychosis was less common in males than females. The mean age of onset for psychotic males was significantly lower than psychotic females. CONCLUSION This result implies that developmental physiology underlying psychosis in bipolar illness may differ for men and women. The different proportions of males and females in the study samples may account for conflicting results reported in the literature for age of onset of psychotic bipolar illness.

Effect of lithium on phosphoinositide metabolism in human brain: A proton decoupled 31P magnetic resonance spectroscopy study

BACKGROUND The objective of our study was to evaluate whether lithium increases brain phosphomonoester (PME) levels in human subjects. METHODS Proton decoupled (31)P magnetic resonance spectra were obtained from eight healthy volunteers before and after the administration of lithium carbonate, 450 mg b.i.d., for 7 and 14 days. RESULTS Pairwise comparisons of the mole percent PME revealed a significant increase from baseline at day 7 and day 14 of lithium administration. CONCLUSIONS An increase in PME concentration with 7 and 14 days of lithium administration in the human brain in vivo was observed. Because the inositol-1-monophosphate contributes to the PME peak, this result suggests that some of the initial actions of lithium may occur through a reduction of myo-inositol, which in turn may initiate a cascade of secondary changes at different levels of signal transduction process and gene expression in brain, effects that are ultimately responsible for the therapeutic benefits of lithium.

A cross-over, post-electroconvulsive therapy comparison of clinical recovery from rocuronium versus succinylcholine

STUDY OBJECTIVE To evaluate the effect of the neuromuscular blocking agent, rocuronium, on clinical recovery from electroconvulsive therapy (ECT) as compared with succinylcholine. DESIGN Cross-over study. SETTING University hospital. PATIENTS 13 ASA physical status I and II patients, ages 18 to 60 years, receiving ECT three times a week. INTERVENTIONS Each patient received either succinylcholine before the first ECT session (Group S) and rocuronium before the third ECT session (Group R). Muscle paralysis was produced with succinylcholine one mg kg(-1) intravenously (IV) or rocuronium 0.3 mg kg(-1) IV. Reversal of the residual neuromuscular block (Group R) was accomplished with 10 microg kg(-1)of atropine and 20 microg kg(-1)of neostigmine after completion of the ECT procedure. MEASUREMENTS Motor seizure duration time, time to first spontaneous breathing, eye opening, head lift, and tongue depressor test were recorded. MAIN RESULT Motor seizure duration and time to first spontaneous breath was longer (33.6 sec vs. 24.2 sec; 9.46 min vs 8.07 min, respectively) in the rocuronium group than the succinylcholine group. No significant difference was detected between the two groups in eye opening, head lift, or tongue depressor testing. CONCLUSION Rocuronium, when used in conjunction with a reversal agent, may be an adequate alternative to succinylcholine as a neuromuscular blocker during ECT.

Characteristics of rapid cycling bipolar-I patients in a bipolar speciality clinic

OBJECTIVES To investigate the characteristics of patients with rapid cycling bipolar illness. METHODS The charts of bipolar patients treated at the Massachusetts General Hospital Bipolar Clinic were reviewed for age of the first affective episode, demographics and history of rapid cycling. RESULTS Data from 223 bipolar-I-II patients, of whom 11.7% were bipolar-II, were obtained, and only the data from 197 bipolar-I patients were analyzed. Forty-three percent of them had a positive history of rapid cycling. Rapid cycling was more common in women, with rapid cycling females having an earlier age of onset than non-rapid cycling bipolar-I females. No such association was found in bipolar-I males. In addition, with respect to current age, rapid cyclers were younger than non-rapid cyclers in bipolar-I females. No association was found for duration of illness. CONCLUSIONS Women with bipolar-I illness have an increased probability of rapid cycling, which may still be increased in those with an early onset. Therefore, biological factors, such as sex and age onset, appear to be relevant to the physiology of rapid cycling. The retrospective design and the selected population of bipolar-I patients from an academic tertiary-referral center may limit the generalizability of our results.